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The synthetic antimicrobial peptide 19-2.5 attenuates septic cardiomyopathy and prevents down-regulation of SERCA2 in polymicrobial sepsis.

ABSTRACT: An impairment of cardiac function is a key feature of the cardiovascular failure associated with sepsis. Although there is some evidence that suppression of sarcoplasmic reticulum Ca²⁺-ATP-ase (SERCA2) contributes to septic cardiomyopathy, it is not known whether prevention of the down-regulation of SERCA2 improves outcome in sepsis. Thus, we investigated whether the administration of the synthetic antimicrobial peptide Pep2.5 may attenuate the cardiac dysfunction in murine polymicrobial sepsis through regulating SERCA2 expression. We show here for the first time that the infusion of Pep2.5 reduces the impaired systolic and diastolic contractility and improves the survival time in polymicrobial sepsis. Preservation of cardiac function in sepsis by Pep2.5 is associated with prevention of the activation of NF-?B and activation of the Akt/eNOS survival pathways. Most notably, Pep2.5 prevented the down-regulation of SERCA2 expression in a) murine heart samples obtained from mice with sepsis and b) in cardiomyocytes exposed to serum from septic shock patients. Thus, we speculate that Pep2.5 may be able to prevent down-regulation of cardiac SERCA2 expression in patients with sepsis, which, in turn, may improve cardiac function and outcome in these patients.

SUBMITTER: Martin L

PROVIDER: S-EPMC5112529 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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The synthetic antimicrobial peptide 19-2.5 attenuates septic cardiomyopathy and prevents down-regulation of SERCA2 in polymicrobial sepsis.

Martin Lukas L Horst Klemens K Chiazza Fausto F Oggero Silvia S Collino Massimo M Brandenburg Klaus K Hildebrand Frank F Marx Gernot G Thiemermann Christoph C Schuerholz Tobias T

Scientific reports 20161117

An impairment of cardiac function is a key feature of the cardiovascular failure associated with sepsis. Although there is some evidence that suppression of sarcoplasmic reticulum Ca<sup>2+</sup>-ATP-ase (SERCA2) contributes to septic cardiomyopathy, it is not known whether prevention of the down-regulation of SERCA2 improves outcome in sepsis. Thus, we investigated whether the administration of the synthetic antimicrobial peptide Pep2.5 may attenuate the cardiac dysfunction in murine polymicrob ...[more]

PMID: 27853260

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Project description:The development of cardiac dysfunction caused by microbial infection predicts high mortality in sepsis patients. Specialized pro-resolving mediators (SPMs) mediate resolution of inflammation in many inflammatory diseases, and are differentially expressed in plasma of sepsis patients. Here, we investigated whether the levels of SPMs are altered in the murine septic heart following polymicrobial sepsis-induced cardiac dysfunction. Ten weeks-old male C57BL/6 mice were subjected to polymicrobial sepsis induced by cecal ligation and puncture (CLP), which is a clinically relevant sepsis model receiving analgesics, antibiotics, and fluid resuscitation. CLP caused a significant systolic dysfunction assessed by echocardiography. The hearts were subjected to LC-MS/MS based lipid mediator profiling. Many SPMs were significantly reduced in septic hearts, among which RvE1 had a ~93-fold reduction. Treatment of CLP mice with synthetic RvE1 (1 μg/mouse i.v.) at 1 h after CLP increased peritoneal macrophages number, particularly MHC II- macrophages. RvE1 reduced pro-inflammatory gene expression (interleukin-1β, interleukin-6, and CCL2) in lipopolysaccharide-stimulated bone marrow-derived macrophages (BMDMs) in vitro. RvE1 attenuated cardiac dysfunction in septic mice and increased cardiac phosphorylated Akt; decreased cardiac phosphorylated IκB kinase α/β, nuclear translocation of the NF-κB subunit p65, extracellular signal-regulated kinase 1/2, and c-Jun amino-terminal kinases 1/2. Most notably, RvE1 treatment reduced peritoneal bacterial load and promoted phagocytosis activity of BMDMs. In conclusion, cardiac SPMs, particularly RvE1, are substantially reduced in mice with polymicrobial sepsis. Delayed therapeutic administration of RvE1 to mice with polymicrobial sepsis attenuates the cardiac dysfunction through modulating immuno-inflammatory responses. In addition to the above effects, the ability to enhance bacterial clearance makes RvE1 an ideal therapeutic to reduce the sequalae of polymicrobial sepsis.

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Dataset Information

The synthetic antimicrobial peptide 19-2.5 attenuates septic cardiomyopathy and prevents down-regulation of SERCA2 in polymicrobial sepsis.

Publications

The synthetic antimicrobial peptide 19-2.5 attenuates septic cardiomyopathy and prevents down-regulation of SERCA2 in polymicrobial sepsis.

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